The drug ranitidine, chemically identified as N-[2-[[[5-(dimethyl-amino)methyl-2-furany]methyl]thio]ethyl]-N'-methyl-2-n itro-1,1-ethenediamine and its physiologically acceptable salts are described and claimed in U.S. Pat. No. 4,128,658, and a particular crystalline form of ranitidine hydrochloride is described and claimed in U.S. Pat. No. 4,521,431 (both incorporated herein by reference). In both these patents there is reference to formulations for oral administration, which may, for example, be in the form of tablets, capsules, granules powders, solution, syrups, suspensions, or tablets or lozenges for buccal administration. Oral preparations of ranitidine are also disclosed in U.S. Pat. Nos. 4,585,790, 4,880,636, 5,028,432, 5,068,249 and 5,102,665. As used herein the term "ranitidine" refers to both the free base and the pharmaceutically acceptable acid addition salts thereof unless otherwise noted.
Ranitidine is an antagonist to histamine H.sub.2 receptors. This drug is widely used in the treatment of duodenal ulcers in humans in the form of the hydrochloride salt. While the drug is generally given orally or by injection, the oral route is preferred. Ranitidine HCI is sold under the trademark Zantac.RTM. by Glaxo Inc. of Research Triangle Park, North Carolina.
Recently ranitidine has been approved by the FDA for treatment of esophagitis. The patient suffering with esophagitis is effectively treated by administration of 150 mg of ranitidine four times a day. However, the four times a day dosing regime often leads to poor patient compliance. Studies have shown that patient compliance increases as the dosing regime goes from four times a day to twice or once a day. Therefore, a dosage form that reduces the ranitidine daily dosing regime, while maintaining a stable plasma level of ranitidine, i.e., a sustained release form, would be advantageous.
Clinically acceptable sustained release forms of ranitidine using conventional technology have not heretofore been successful. Ranitidine has 50% absolute bioavailability, and it is only absorbed in the initial part of the small intestine. These properties are not favorable for sustained release delivery means.
Numerous patents teach a sustained drug release system and list ranitidine as a suitable candidate. However, such systems do not allow for the peculiar properties of ranitidine and thus yield less than ideal sustained release formulations. That is, these systems do not allow for the balance that must be made between the amount of the drug immediately released and the amount of time over which the remaining drug in the sustained release (SR) portion is released. For example, if too much ranitidine is present in the immediate release (IR) portion, the result is essentially the same as that obtained with the commercially available tablets, i.e., an immediate release formulation. Conversely, if too little ranitidine is present in the immediate release portion, the resulting formulation exhibits poor bioavailability.
Multi-layer, solid drug formulation have been known in the pharmaceutical art for several years. These formulations usually consisted of coated tablets and pellets or multiple-layer tablets (either bi- or tri-layer tablets). Usually the layers are "built-up" with multiple coatings on a tablet core, a process widely practiced in this art. Examples of the application of multi-layer drug formulation to improve the in vivo activity of a drug are given by Kim, et. al. (U.S. Pat. No. 4534973) and Leslie, S. T., et. al. (Pharmaceutical 2(3), pp. 192-194, 1979). The use of multi-layer drug formulations (either as multiple layer tablets or coated tablets or pellets) have been used to sustain the blood level of various drugs. Examples of these types of systems have been applied to theophylline, phenylpropanolamine, aspirin, and many others. In practically all cases, this approach has been applied to drugs that are well absorbed and drugs that are absorbed throughout the entire gastro-intestinal tract.